Clinical courses of 24,563 hospitalized COVID-19 patients during the first 12 months of the pandemic in the Central City of Iran

This study was designed and implemented to analyze and establish documents related to the above cases in the first to third COVID-19 epidemic waves for the use of researchers and doctors during and after the epidemic. The current case series study was conducted on 24,563 thousand hospitalized COVID-19 patients by examining their clinical characteristics within a one-year period from the beginning of the pandemic on 02.22.2020 to 02.14.2021, which included the first to the third waves, based on gender and severity of COVID-19. The mean age of the participants was 56 ± 20.71, and 51.8% were male. Out of a total of 24,563 thousand hospitalized COVID-19 patients until February 2021, there were 2185 mortalities (9.8%) and 2559 cases of severe COVID-19 (13.1%). The median length of hospitalization from the time of admission to discharge or death in the hospital (IQR: 13–41) was estimated to be 21 days. The rate of hospital mortality was higher in severe (37.8%) than in non-severe (4.8%) cases of COVID-19, While the risk of severe cases increased significantly in the third (HR = 1.65, 95% CI: 1.46–1.87, P < 0.001) and early fourth waves (HR = 2.145, 95% CI: 1.7–2.71, P < 0.001). Also, the risk of contracting severe COVID-19 increased significantly in patients aged ≥ 65 years old (HR = 2.1, 95% CI 1.1.93–2.72, P < 0.001). As shown by the results, the rates of hospital mortality (9.3% vs. 8.5%) and severe cases of COVID-19 (13.6% vs. 12.5%) were higher among men than women (P < 0.01). In our study, the mortality rate and severity of COVID-19 were within the scope of global studies. Men experienced higher severity and mortality than women. The was a significantly higher prevalence of old age and underlying diseases in individuals with severe COVID-19. Our data also showed that patients with a previous history of COVID-19 had a more severe experience of COVID-19, while most of these patients were also significantly older and had an underlying disease.

www.nature.com/scientificreports/ Hospitalized patients were classified as severe and non-severe. Severe cases of COVID-19 were considered based on one of the following criteria: ≤ 85% blood oxygen level or airway intubation. Statistical analysis. Demographic-clinical characteristics of patients admitted to the hospital due to COVID-19 were reported using descriptive statistics (mean ± SD), median, and frequency (%). Demographicclinical characteristics of hospitalized patients were described and compared by sex and severity of the COVID-19 disease using chi-square, t-test, and ANOVA or its non-parametric equivalent. We used of log-rank test to comparison different median hospital survival in patients and performed cox model for to assess the association between variables with dependent variable. The primary event of interest was in-hospital mortality, severity. The significance level of the test was considered to be 5%. Analysis was performed using R software version 4.2.2 and IBM SPSS Statistics for Windows, Version 26.0. software. Patient and public involvement. Patients and/or the public were not involved in design, plan, manage and carry out research.
Ethics approval and consent to participate. The present study was ethically approved by the Shahid-Sadoughi University of Medical Sciences' ethics committee (ethics code: IR.RUMS.REC.1399.017). All provisions of the Declaration of Helsinki adhered in our study, especially appropriate ethical and scientific review. All patients signed a predefined consent specially their clinical data usage.

Results
Overall, 24,563 hospitalized patients with COVID-19 were admitted within 12 months. The mean age of these patients was 56. 20 ± 20.71 years and in the range of (0-127) years (infant less than one year). Sexual distribution was male (51.5%), and 95.3% were Iranian. Out of the population under study, 4.85% were referred to the hospital in person, and 9.9% were transferred to the hospital using the services of the emergency medical system.
Demographic and clinical characteristics of patients by gender are presented in Table 1. Table 1 shows that most patients were young and < 65 years old, with women admitted more than men in this age group. However, men were admitted more than women in the age group ≥ 65 years (P < 0.001). About 1.3% (n = 165) of patients reported a previous history of the COVID-19 infection, with women reporting a prior history of the COVID-19 infection more than men. Yet, the recurrence of the COVID-19 infection was not affected by gender. Most patients presented with clinical complaints of abdominal pain, dizziness, cough, dyspnea, fever, and muscle aches. Women reported more chest pain, nausea, vomiting, and muscle aches, while men reported fever and unconsciousness (P < 0.05). The highest prevalence of underlying diseases was reported in patients with diabetes, hypertension, and cardiovascular diseases. Underlying cardiovascular disease, hypertension, diabetes, asthma, and congenital disorders were more common in women, while COPD was more prevalent in men (P < 0.01). Men reported a more significant history of smoking and drug use than women. According to the hospitalization indication, most patients were admitted with a positive PCR diagnostic test, the majority of whom were hospitalized (P < 001.0). Overall, 28.6% (7023 patients) were admitted to the hospital with a clinical diagnosis, and men were hospitalized significantly more than women in all hospitalization indications (P = 0.003). The mean body temperature of men was considerably higher than that of women (P = 0.01). Men were significantly more likely than women to be treated with ventilators and dialysis (P = 03.0). Severe cases of COVID-19 and mortality were significantly higher in men than women.
Demographic and clinical characteristics of patients based on the severity of COVID-19 are presented in Table 2.
Of the total patients, 13.1% experienced severe COVID-19 infection. Table 2 shows that patients ≥ 65 years of age experienced more severe infections with COVID-19 than younger patients (P < 0.001). Patients with a history of the COVID-19 infection and those exposed to other patients experienced more severe infections with COVID-19 (P < 0.001). Most clinical complaints in severe cases were related to respiratory symptoms, and the lowest was associated with nervous system symptoms. Patients with severe COVID-19 infection reported more clinical signs associated with the respiratory, gastrointestinal, and nervous systems than non-severe cases (P < 0.01).
Accordingly, the most common clinical symptoms observed in patients with severe COVID-19 included anesthesia, seizures, paralysis, pelegia, and shortness of breath, while patients with a history of COPD underlying disease, neurological disorders, cancer, drugs, cardiovascular disease, hypertension, diabetes, and asthma were more likely to develop severe COVID-19 (P < 0.01).
The mean body temperature of patients with severe COVID-19 was significantly higher than that of nonsevere cases of COVID-19 (P < 0.001). Patients treated with oxygen therapy had more severe cases of infection than those without oxygen therapy (P < 0.001).
Most patients were admitted with a positive PCR diagnostic test based on the hospitalization indication. According to the hospitalization indication, more than 16% of patients admitted with a positive PCR diagnostic test experienced severe COVID-19 infection (P < 0.001). The prevalence of death was significantly higher in severe (37.8%) compared to non-severe patients (4.8%) (P < 0.001, Fig. 1). More women were hospitalized with a positive PCR test and men with a positive CT scan (P < 0.001). Table 3 show means and medians for survival time of hospitalization from admission to death/discharge in hospitalized patients' death. Table 3 presents the median length of hospitalization and the risk of severe COVID-19 infection. According to the results of the Kaplan-Meier method, the median length of hospitalization from the time of admission to discharge or death in the hospital (IQR: 13-41) was estimated to be 21 days. As shown by the results of the logrank test, the median hospital survival was significantly lower in patients aged ≥ 65 years (16 days) compared to younger patients (30 days) and in severe cases of COVID-19 (13 days) compared to non-severe cases ( www.nature.com/scientificreports/ (P < 0.001). Also, the median hospital survival was significantly different between the pandemic waves, decreasing by 19 and 15 days in the third and early fourth waves, respectively (P < 0.001). The results of univariate Cox regression showed that the risk of contracting severe COVID-19 in hospitalized patients significantly increased by 1.65 and 2.14 times in the third and early fourth waves. Also, the risk of contracting severe COVID-19 was significantly higher in patients aged ≥ 65 years (HR = 2.1) than in younger people (P < 0.001). Figure 2 presents the median length of hospitalization from admission to death/discharge in hospitalized patients' death using the Kaplan-Meir method based on age, sex, pandemic waves, severity (Fig. 3).

Discussion
The data set used in this study was collected from the date of onset of the COVID-19 pandemic from February 22, 2020, to 13 February 13, 2021 from the MCMC hospital registration system. During this period, Iran has identified three waves of the COVID-19 pandemic with the predominant strain of the Wuhan virus, along with the fourth COVID-19 wave in late February 2021. This study described the clinical features and hospital survival of patients based on age, gender, and severity of COVID-19 during the 12 months following the onset of the pandemic.
Our analyses showed that out of 24,563,000 patients with COVID-19, admitted until February 13, 2021, 2185 patients (8.9%) died, and the median survival of the hospital was estimated to be 21 days using the Kaplan-Mayer method. Also, 2559 patients (13.1%) were identified as severe cases of COVID-19. The majority of patients were admitted with a positive PCR test. As observed, the gender distribution of COVID-19 was similar to other studies, with men were more affected than women 8,19 . According to the systematic review and meta-analysis report on 15,828 cases of COVID-19, the prevalence of severe and critical cases was 17.84% and 4.9%, respectively 9 . However, our study showed lower values (13.1%), which may be due to the lack of data related to the hospitalization in the intensive care unit. The severity and hospital mortality of COVID-19 were also affected by gender 20 .
In line with other studies, men experienced a worse prognosis than women 21,22 .
The World Health Report has shown 3.0-8.35 higher mortality rate for men than women 23 . Also, according to evidence from different studies, biological differences in gender affect the severity and outcomes of COVID-19, with men experiencing more severe and worse outcomes [24][25][26] . Our data also showed that the mean age men who died was significantly 2 years higher than the age of the deceased women, highlighting the role of age in the severity of COVID-19 outcomes in line with other studies 22,27 . Also, differences in age, gender, ethnicity, geographical location, and social and cultural structure affect the severity of the disease and its mortality 28,29 .
The most common underlying diseases in hospitalized COVID-19 patients were diabetes, hypertension and heart disease 30,31 . were more at risk of severe COVID-19 cases than others 32 .
Our findings, similar to previous studies, showed that the most common clinical symptoms were fever, cough, and shortness of breath 2,8,33,34 . The prevalence of clinical signs of fever 35 , anesthesia, and the headache was significantly higher in men, while women reported higher prevalence of chest pain, nausea, vomiting, muscle pain, plegia, dizziness, and skin symptoms. In general, respiratory, gastrointestinal, and neurological symptoms were more common in men than women, but the prevalence of clinical symptoms was not affected by gender. Wang et al. reported that clinical signs of fever, cough, and chills were more common in men. Only 35% of patients reported a history of contact with COVID-19 patients, with men showing a significantly higher likelihood for such a contact than women. Besides, these patients experienced severe cases COVID-19 about three time more than the others 36 . Another study in the early stages of the epidemic in China reported that 23% of severe cases had a history of exposure to areas of epidemic onset 20 . Another preliminary study from China also reported that 72.3% of those infected were in contact with Wuhan residents 37 . In another study, Hong et al. found that 70% www.nature.com/scientificreports/ of patients had a history of close contact with COVID-19 patients 36 . The results showed that people who had close contact with the patients two days before and three days after the onset of the symptoms were 3.1 times more likely to be at high risk 38 . Compared with asymptomatic patients, those exposed to patients with mild symptoms were 4 and 3.4 times more likely to be at risk than those exposed to moderate cases of the disease 38 .
The results showed that the patient's viral load decreased to its full two days before the onset of symptoms and after one week 38  Duration of hospitalization has been reported based on the average or median in different studies. In a study by Nirmala while, the average length of hospital stay was between 4 to 53 days in 45 hospitals in China and 4-21 in studies outside China, as found in a meta-analytical study with 52 studies (46 studies from China) 43 Also, the median length of hospital stay was 7 days (in a study from Iran 44 , 12 days in a study by Nirmala 45 , and 12.4 days using the AF methods 46 .
We found that the length of hospitalization of COVID-19 patients was influenced by gender. Consistent with other studies, our results showed that the duration of hospitalization was longer in severe than non-severe cases 27 , with patients who experienced severe cases of COVID-19 hospitalized three days more than those without severe COVID-19. The length of hospitalization has been reported differently in various studies, and factors such as the severity of the disease, the time from the onset to the diagnosis, age over 45 years, residential area 47 , previous underlying medical conditions, and the location of the infection 48 affect the length of hospital stay of COVID-19 patients.
Our findings showed that most of patients had a respiratory rate of 14-18 beats per minute, . CT scans also showed about 91% of patients with lung abnormalities Our findings showed that the results of positive CT scans of patients with severe cases of COVID-19 lung involvement were significantly higher than the others.. One of Table 2. Clinico-demographic profile of patients based on the severity of COVID-19. *P < 0.05.  Table 3. Means and medians for survival time. *P < 0.001, Log-rank test. www.nature.com/scientificreports/ the the essential tools for assessing of COVID-19 severity is the CT scan results of the lungs 27 . Studies have also shown that the respiratory pattern in COVID-19 is not similar to that of the flu and cold, according to which people with COVID-19 have faster breathing due to shortness of breath 8,38 . Liu et al. noted that patients with severe COVID-19 infections were more prone to faster respiration 8 and higher respiration rates. According to another study, a decrease in the vital respiratory capacity was observed in 65.4%, while 18.8% of patients represented an abnormal respiratory pattern 38 .

P-value
Previous studies have reported that decreased blood oxygen levels were associated with increased severity of COVID-19 8,41 . Studies have shown that the objective symptoms of respiratory distress-oxygen saturation and respiratory rate-are associated with worse outcomes, such as a significant increase in mortality 27 . Chatterjee et al. reported that the chance of mortality in patients with a respiratory rhythm of > 22 beats per minute was 2.3-9.1 times higher than in patients with a normal respiratory rhythm (< 20 beats per minute) 27 . The results of these studies confirm our epidemiological findings.
The mean body temperature of men compared with women and the body temperature of patients with severe COVID-19 also increased significantly compared to the others.. One of the most common clinical signs of COVID-19 infection is fever, which leads to an increase in body temperature 49,50 and can be considered one of the screening tools to diagnose COVID-19 infection in communities 50 . Wang et al. reported that severe cases of COVID-19 increased significantly in patients with febrile symptoms 50 , while another study reported that severe cases of COVID-19 had higher body temperature 8 . In another study, it was reported that the mortality rate in patients with an average body temperature of more > than 40° C was 42% 51 which confirms our findings.
About 5% of the COVID-19 patients admitted to the hospital received treatment with mechanical ventilation.. In other studies, age was high in patients undergoing mechanical ventilation, and elderly patients suffered from underlying diseases, etc. 52 . Our data showed that patients treated with mechanical ventilation were, average nine years older than those without mechanical ventilation treatment.Patients treated with mechanical ventilation experience higher mortality 53 . Consistent with our study, mortality was higher in patients with severe COVID-19. Men also experienced more cases of COVID-19 than women on dialysis.
The results of our study showed that most cases occurred in the third wave of COVID-19 (50.1%) with 12,318 infections, according to which the distribution of severe cases of COVID-19 increased significantly from 7.6% in the first wave to 9.4% during the second wave. It then decreased during the third wave (15.7%) and then decreased significantly at the beginning of the fourth wave 13% in late February. As seen in each wave, the prevalence severs of COVID-19 was inversely related to number of admitted patients.
However, the gender distribution did not differ significantly during the COVID-19 pandemic waves. In addition to mutations in the COVID-19 virus and changes in its transmission, other factors such as social events, the end of quarantine, gathering in enclosed places, etc. led to numerous waves of COVID-19 in many countries with different intensities and characteristics 1 . As spainish study reported that the number of hospitalizations increased from 204 in the first wave to 264 in the second wave 1 . On the other hand, the duration of hospitalization in the second wave was shorter than in the first wave 1 .
Based on the results of the log-rank test, the duration of hospitalization decreased significantly from 25-28 days in the first and second waves to 19 days in the third and 15 days in the early fourth wave in late February. It seems, it was because of admission indications were changed during first year of COVID-19 pandemic so   www.nature.com/scientificreports/ that in the later wave the sever patients were admitted more than in the early wave. This changes in severity of COVID-19 can be due to admission criteria changes during pandemic. Our analysis showed that the risk of severe cases was 1.65 and 2.14 times higher than the first wave of COVID-19 in the third and early fourth wave to the end of February 2021 can be explained by admission criteria strategies changes during pandemia and previous exposure to COVID-19 as predictors of severity of disease. Also, the risk of severe cases of COVID-19 was 2.1 times higher in patients aged ≥ 65 years than in younger people.

Conclusion
According to evidence obtained in our study, the mortality rate and severity of COVID-19 were comparative with world experiences. The incidence and mortality rate was higher in the elderly ,men, those with a history of underlying diseases. Our data also showed that patients with a previous history of COVID-19 had a more severe experience of COVID-19. In addition, based on the hospitalization indication, the hospitalized patients with positive PCR test experienced the most severe COVID-19 . During first year of pandemia we saw the risk of severe cases in the third and early fourth wave were 1.654 and 2.148 times higher than the first wave of COVID-19.

Strengths and weaknesses.
One of the limitations of the present study is the lack of data related to hospitalization in the intensive care unit, which is one of the cases in the category of diagnosis of severe cases of COVID-19 and may have led to underestimating the prevalence of severe cases of COVID-19 in our study. Other topics include failure to record the time of the onset of clinical symptoms as one of the factors affecting the severity of COVID-19 is hospitalization. One of the strengths of the present study is the selected duration of time and the high volume of data.

Data availability
Availability of these data, was under license for the current study, and so is not publicly available. The data that support the findings of this study are available from Shahid Sadoughi University of Medical Sciences but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of